This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia.
International Patent Application WO 89/05297 discloses a number of substituted quinazoline compounds which are indicated as inhibitors of gastric acid secretion.
According to the present invention, there is provided a compound of formula I, 
wherein
R1 represents C1-4 alkoxy optionally substituted by one or more fluorine atoms;
R2 represents H or C1-6 alkoxy optionally substituted by one or more fluorine atoms;
R3 represents one or more groups independently selected from H, halogen, C1-4 alkoxy and CF3;
in addition, R2 and one R3 group may together represent xe2x80x94OCH2xe2x80x94, the methylene group being attached to the ortho-position of the pendant phenyl ring;
R4 represents a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen, SO2NR8R9 and NHSO2(C1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;
R8 and R9 independently represent H or C1-4 alkyl;
X represents CH or N; and
L is absent,
or represents a cyclic group of formula Ia, 
in which N is attached to the 2-position of the quinoline or quinazoline ring;
A is absent or represents CO or SO2;
Z represents CH or N;
m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and
n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5;
or represents a chain of formula Ib, 
in which N is attached to the 2-position of the quinoline or quinazoline ring;
Axe2x80x2 and Zxe2x80x2 have the same significance as A and Z above, respectively;
R6 and R7 independently represent H or C1-4 alkyl; and
p represents 1, 2 or 3, and in addition, when Zxe2x80x2 represents CH, it may represent 0;
or a pharmaceutically acceptable salt thereof (referred to together herein as xe2x80x9cthe compounds of the inventionxe2x80x9d).
Pharmaceutically acceptable salts include acid addition salts, such as hydrochloride and hydrobromide salts, and phosphate salts.
Alkyl and alkoxy groups that R1-4 may represent or include can be straight chain, branched chain, cyclic, or a combination thereof
Heterocyclic groups that R4 represents may be saturated or unsaturated.
The compounds of the invention may be optically active. In particular, they may exhibit atropisomerism about the bond joining the pendant phenyl ring to the rest of the molecule when an R3 substituent is in the 2- or 3-position of the phenyl ring. The invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof.
Preferred groups of compounds that may be mentioned include those in which:
(a) R1 represents methoxy;
(b) R2 represents methoxy;
(c) R2 and an R3 group together represent xe2x80x94OCH2xe2x80x94;
(d) R3 represents H or 4-fluoro;
(e) R4 represents a group having the formula II, III, IV, V or VI, 
xe2x80x83wherein
Y represents O, CH2, SO2, NR5 or CHF; and
R5 represents H or C1-4 alkyl;
the group of formula II being of particular interest, especially when Y represents O; and
(f) L represents a group of formula VII, 
xe2x80x83or is absent, this latter preference being of particular interest when R4 represents a group of formula V or VI.
According to the invention, there is also provided a process for the production of a compound of the invention, which comprises:
(a) when X represents CH, cyclizing a compound of formula X, 
xe2x80x83in which R1-4 and L are as defined above;
(b) when A or Axe2x80x2 is present, and Z or Zxe2x80x2 represents N, reacting a compound of formula XIIIa or XIIIb, as appropriate, 
xe2x80x83in which R1-3, R6, R7, X, m, n and p are as defined above, with a compound of formula XIV, 
xe2x80x83in which R4 is as defined above, Axe2x80x2 represents CO or SO2 and Lg represents a leaving group;
(c) reacting a compound of formula XVIII, 
xe2x80x83in which R1, R2, R4, X and L are as defined above, with a compound of formula XIX, 
xe2x80x83in which R3 is as defined above; or
(d) when X represents N, reacting a compound of formula XXII, 
xe2x80x83in which R1-3 are as defined above, with a compound of formula XXIIIa or XXIIIb, as appropriate, 
xe2x80x83in which R4, R6, R7, A, Axe2x80x2, Z, Zxe2x80x2, m, n and p are as defined above;
(e) when A or Axe2x80x2 represents CO, reacting a compound of formula XXVIIIa or XXVIIIb, as appropriate, 
xe2x80x83in which R1-3, R6, R7, X, Z, Zxe2x80x2, m, n and p are as defined above, and Lg is a leaving group, with a compound of formula XXIX,
HR4axe2x80x83xe2x80x83XXIX
xe2x80x83in which R4a represents the groups defined by R4 above which contain a nucleophilic nitrogen atom in the ring, this nucleophilic nitrogen atom being attached to H;
(f) conversion of a compound of formula I in which L represents a cyclic group of formula Ia, to a corresponding compound of formula I in which L represents a chain of formula Ib in which R6 and R7 each represent H, by the action of a strong base;
(g) when A or Axe2x80x2 is absent and Z or Zxe2x80x2 represents N, reacting a compound of formula XIIIa or XIIIb, as defined above, with a compound of formula XXX,
R4-Halxe2x80x83xe2x80x83XXX
xe2x80x83in which R4 is as defined above and Hal represents a halogen atom attached to the ring; or
(h) when R2 and one R3 group together represent xe2x80x94OCH2xe2x80x94, cyclization of a compound of formula XXXI, 
xe2x80x83in which R1, R4, X and L are as defined above, and R3a has the same meaning as R3 above except that R2 and an R3a group do not together represent xe2x80x94OCH2xe2x80x94;
xe2x80x83a and where desired or necessary converting the resulting compound of the invention into a pharmaceutically acceptable salt or vice versa.
In process (a), the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent which does not adversely affect the reaction (for example tetrahydrofuran) around room temperature and quenched with water.
In process (b), suitable leaving groups are OH and Cl. When the compound of formula XIV is a carboxylic acid, the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH2Cl2) at or around room temperature. When the leaving group is Cl. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2) around 0xc2x0 C.
In process (c), the reaction may be carried out in the presence of a palladium catalyst [for example tetrakis(triphenylphosphine)palladium] in a solvent which does not adversely affect the reaction (for example a mixture of toluene, ethanol and 1N aqueous sodium carbonate) at an elevated temperature (for example the reflux temperature of the solvent).
In process (d), the reaction may be carried out in a solvent which does not adversely affect the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example 100xc2x0 C.).
In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature.
The reaction may also be carried out without isolating the compound of formula XXVIIIa or XXVIIIb, by reacting a compound of formula XIIIa or XIIIb with triphosgene and a compound of formula XXIX. In this case the leaving group is xe2x80x94Cl. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2) in the presence of a base (for example triethylamine) at or around room temperature.
In process (f), suitable strong bases include lithium diisopropylamide. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example THF).
In process (g), the reaction may be carried out in a solvent which does not adversely affect the reaction (for example a mixture or n-BuOH and dimethylacetamide) in the presence of a base (for example triethylamine) at an elevated temperature (for example 80xc2x0 C.).
In process (h), suitable reagents are sodium carbonate with palladium acetate. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example dimethylacetamide) at an elevated temperature (for example 130xc2x0 C.).
It will be apparent to those skilled in the art that in the processes described above [for example process (c)], and in the methods given below for preparation of the starting materials used in the above processes, when R2 and R3 are present in different molecules, they cannot together represent xe2x80x94OCH2xe2x80x94.
Compounds of formula X [see process (a)] may be prepared by reaction of a compound of formula XI, 
in which R1-3 are as defined above, with a combination of a compound of formula XII, 
in which R4 and L are as defined above, and phosphorous oxychloride in dichloromethane at the reflux temperature of the solvent.
Compounds of formula XIIIa or XIIIb [see process (b)] in which X represents CH may be prepared from compounds of formula XVa or XVb, as appropriate, 
in which R1-3, R6, R7, m, n and p are as defined above, by bubbling HCl gas through a solution of the compound in dichloromethane.
Compounds of formula XVa or XVb may be prepared from compounds of formula XVIa or XVIb, as appropriate, 
in which R1-3, R6, R7, m, n and p are as defined above, by cyclization using potassium hydroxide or lithium diisopropylamide at an elevated temperature (such as 90xc2x0 C.) in DMSO, quenching with water.
Compounds of formula XVIa or XVIb may be prepared by reacting a compound of formula XI, as defined above, with a compound of formula XVIIa or XVIIb, as appropriate, 
in which R6, R7, m, n and p are as defined above, by the method described above for producing compounds of formula X.
Compounds of formula XIIIa or XIIIb in which X represents N may be prepared by reacting a compound of formula XXII, 
in which R1-3 are as defined above, with a compound of formula XXIIa or XXIIb, as appropriate, 
in which R6, R7, m, n and p are as defined above, using the conditions mentioned for process (d) above.
Compounds of formula XVIII [see process (c)] in which X represents CH may be prepared by cyclization of a compound of formula XX, 
in which R1, R2, R4 and L are as defined above, using the reaction conditions mentioned in process (a) above.
Compounds of formula XX may be prepared by reacting a compound of formula XXI, 
in which R1 and R2 are as defined above, with a compound of formula XII as defined above, using the method described above for the preparation of compounds of formula X.
Compounds of formula XVIII in which X represents N may be prepared by reacting a compound of formula XXVII, 
in which R1 and R2 are as defined above, with a compound of formula XXIIIa or XXIIIb, as appropriate, as defined above, using the reaction conditions mentioned above for process (d).
Compounds of formula XXII [see process (d)] may be prepared from a compound of formula XXIV, 
in which R1-3 are as defined above, by reaction with a saturated solution of ammonia in methanol.
Compounds of formula XXIV may be prepared from a compound of formula XXV, 
in which R1 and R2 are as defined above, by reaction with a compound of formula XIX as defined above using the reaction conditions described above for process (c), followed by reaction with POCl3 and N,N-dimethylaniline.
Compounds of formula XXV may be prepared from a compound of formula XXVI, 
in which R1 and R2 are as defined above, using conventional techniques.
Compounds of formula XXVIIIa and XXVIIIb [see process (e)] in which Lg represents Cl may be prepared from compounds of formula XIIIa or XIIIb, as appropriate, by reaction with triphosgene. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2) in the presence of a base (for example triethylamine) at around xe2x88x9210xc2x0 C.
Compounds of formula XXXI [see process (h)] may be prepared from compounds of formula XXXII, 
in which R1, R4, L and X are as defined above, by reaction with a compound of formula XXXIII, 
wherein R3a is as defined above, in the presence of sodium hydride in DMF at room temperature.
Compounds of formula XXXI are analogous to compounds of formula I, and may be prepared using analogous methods. For example, when X represents CH, the compounds may be prepared by cyclizing a compound analogous to those of formula X using process (a). When X represents N, the compounds may be prepared from a compound analogous to those of formula XXI and a compound of formula XXIIIa or XXIIIb, as appropriate, using process (d).
Compounds of formulae XI, XII, XIV, XVIIa, XVIIb, XIX, XXI, XXIIa, XXIIb, XXIII, XXVI, XXIX, XXX and XXXIII are either known or are available using known techniques.
The intermediate compounds of formulae X, XIIIa, XIIIb, XVIII, XXII, XXVIIIa, XXVIIIb and XXI form a further aspect of the invention.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional techniques, for example as described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1991.
The compounds of the invention are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaermia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of greatest interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from such a disorder. The use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of benign prostatic hyperplasia, are also provided.
The compounds of the invention may be administered by any convenient route, for example orally, parenterally (e.g. intravenously, transdermally) or rectally. The daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.01 to 10 mg/kg of body weight, and preferably about 0.05 to 1 mg/kg, is suitable, administered from 1 to 4 times a day.
The compounds of the invention will generally be administered in the form of a suitable pharmaceutical formulation. Thus, according to another aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dose form. Such forms include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles.
Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation in which the active ingredient is uniformly dispersed so that it may be readily subdivided into equally effective unit dosage forms containing typically from 0.1 to about 500 mg of the active ingredient. The solid dosage forms may be coated or otherwise compounded to prolong the action of the formulation.
The formulations of the invention may also contain a human 5-a reductase inhibitory compound [see International Patent Application WO 95/28397], or a compound of the invention could be presented in a pharmaceutical pack also containing a human 5-xcex1 reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use.
The compounds of the invention may be tested in the screens set out below.
Contractile Responses of Human Prostate
Prostatic tissue was cut into longitudinal strips (approximately 3xc3x972xc3x9710 mm) and suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KCl (4.7), CaCl2 (2.5), KH2PO4 (1.2), MgSO4 (1.2), NaHCO3 (25), glucose (11), and gassed with 95% O2/5% CO2. The solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to a sensitising dose of (xe2x88x92)-noradrenaline (100 mM) and washed over a 45 minute period. Isometric contractions were obtained in response to cumulative additions of (xe2x88x92)-noradrenaline to obtain control curves in all tissues. A further curve was then generated in the presence or absence of antagonist (incubated for 2 hours). Antagonist affinity estimates (pA2) were determined using a single concentration of competing antagonist, pA2=xe2x88x92log [A]/(DR-1) where the dose ratio (DR), relative to corresponding controls, was produced by a single concentration of antagonist [A], assuming competitive antagonism and Schild regression close to unity.
Anaesthetised Dog Model of Prostatic Pressure and Blood Pressure
Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg/kg i.v.) and a tracheal cannula was inserted. Subsequent anaesthesia was maintained using pentobarbitone infusion. The animals were respirated with air using a Bird Mk8 respirator (Bird Corp., Palm Springs, Calif., U.S.A.) adjusted to maintain blood gasses in the range pO2 90-110 mm Hg, pCO2 35-45 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5xc2x0 C. using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration. Heart rate was recorded via the lead II E.C.G. A laparotomy was performed to cannulate both ureters to prevent change of fluid volume within the bladder. A 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon was filled with air and the catheter withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments, Quincy, Mass, U.S.A.) and the data measured on line using a Motorola 68000-based microcomputer system (Motorola Inc., Temple, Ariz., U.S.A.). Compounds were made up in PEG 300 and administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 xcexcg/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds were administered (in terms of compound base) at 10-300 xcexcg/kg i.v. 5 min before construction of phenylephrine curves (constructed up to a maximum dose of 128 xcexcg/kg in the presence of test compound).
Due to xcex11-related dysrhythymic properties of phenylephrine, absolute maximal responses were not obtained but were taken as 10% greater than the control response obtained with 16 xcexcg/kg phenylephrine. Drug concentrations were calculated on the basis of molar weight of compound/kg body weight thus allowing a xe2x80x9cpseudo pA2xe2x80x9d calculation by Schild analysis using dose ratios derived from shifts in the phenylephrine dose-response curves.
The compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in benign prostatic hyperplasia without causing undesirable cardiovascular effects, for example because they are able to selectively antagonise prostatic subreceptors of the xcex11-adrenoceptor), or have other more useful properties than the compounds of the prior art.
The invention is illustrated by the following examples, in which the following abbreviations are used:
DMA=dimethylacetamide
DMF=dimethylformamide
DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone
EtOAc=ethyl acetate
EtOH=ethanol
h=hour
MeOH=methanol
min=minute
n-BuOH=n-butanol
THF=tetrahydrofuran
tlc=thin layer chromatography
Intermediate 1
1-(t-Butyloxycarbonyl)-1,4-diazepane
To a solution of homopiperazine (10 g, 1.0 mol) and triethylamine (210 ml, 152 g, 1.5 mol) in CH2Cl2 (500 ml) at 0xc2x0 C. was added a solution of di-(t-butyl) dicarbonate (195 g, 0.89 mol) in CH2Cl2 (300 ml). The mixture was allowed to warm to room temperature and stirred for 18 h after which time the CH2Cl2 was evaporated under reduced pressure. The resulting residue was partitioned between ether and 2N citric acid and the aqueous layer was extracted with ether (4xc3x97200 ml). The aqueous layer was basified with 2N aqueous NaOH and then extracted with CH2Cl2 (4xc3x97400 ml). The combined CH2Cl2 extracts were washed with H2O (2xc3x97), saturated brine (1xc3x97) and dried over MgSO4. Evaporation under reduced pressure followed by azeotroping with CH2Cl2 (4xc3x97) gave the title compound as a yellow waxy solid (94.3 g, 53%). Rf 0.25 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 201 (MH+). Found: C, 58.86; H, 10.03; N, 13.58; C10H20N2O2 0.05.CH2Cl2 requires C, 59.02; H, 9.91; N, 13.70%.
Intermediate 2
1-(t-Butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane
A solution of Intermediate 1 (92.0 g, 0.46 mol) and triethylamine (96.0 ml, 69.7 g, 0.69 mol) in CH2Cl2 (500 ml) at 0xc2x0 C. was treated dropwise with a solution of 4-morpholinecarbonyl chloride (64.0 ml, 82.0 g, 0.55 mol) in CH2Cl2 (100 ml) and the reaction was stirred at room temperature under N2 for 18 h. The reaction mixture was then diluted with CH2Cl2 (400 ml) and washed with 2N citric acid (3xc3x97400 ml), saturated brine (1xc3x97500 ml), dried over MgSO4 and evaporated to give the title compound as an off-white solid (141.7 g, 98%). Rf 0.80 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 314 (MH+). Found: C,57.50; H,8.69; N,13.41; C15H27N3O4 requires C, 57.50; H, 8.69; N,13.41%.
Intermediate 3
1-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride
A solution of Intermediate 2 (140.0 g, 0.44 mol) in CH2Cl2/MeOH (1/1, v/v, 600 ml) at 0xc2x0 C. was saturated with HCl gas and the reaction mixture was stirred at room temperature under N2 for 18 h after which time the reaction mixture was evaporated under reduced pressure and slurried in EtOAc to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with ether and drying in vacuo at 60xc2x0 C. to give the title compound as a colourless solid (99.0 g, 90%). Rf 0.41 (CH2Cl2/MeOH/0.88NH3 84/14/2, v/v). MS m/z 214 (MH+). Found: C, 47.50; H,8.10; N,16.55; C10H19N3O2 HCl 0.2.H2O requires C, 47.41; H, 8.12; N,16.59%.
Intermediate 4
1-Acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane
To a solution of Intermediate 3 (50 g, 0.2 mol) and triethylamine (42 ml, 30.5 g, 0.3 mol) in CH2Cl2 (400 ml) at 5xc2x0 C. was added acetic anhydride (23 ml, 24.9 g, 0.24 mol) dropwise over 15 min and the reaction was then stirred for a further 2 h at room temperature under N2. Dilution with CH2Cl2 (600 ml) was followed by washing with saturated aqueous sodium bicarbonate (2xc3x97200 ml) and the combined aqueous layers extracted with CH2Cl2 (1xc3x97100 ml). The CH2Cl2 layers were combined and washed with saturated brine, dried over MgSO4 and evaporated to give a light brown oil. This was dissolved in CH2Cl2 (300 ml) and treated with triethylamine (8 ml, 5.8 g, 0.06 mol) and EtOH (5 ml), stirred for 1 h at room temperature then washed with saturated sodium bicarbonate and the aqueous layer extracted with CH2Cl2 (5xc3x97). The combined CH2Cl2 layers were dried over MgSO4 and evaporated under reduced pressure to give a yellow oil which was then azeotroped with CH2Cl2 (4xc3x97) to give the title compound as a yellow oil (47.1 g, 92%). Rf 0.45 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 256 (MH+). Found: C,52.62; H,8.18; N,15.02; C12H21N3O3 0.3.CH2Cl2 requires C, 52.61; H, 7.75; N,14.96%.